Obesity confers significant risk for developing type 2 diabetes and metabolic syndrome; however, not all obese individuals develop these metabolic disorders. This implies that factors beyond BMI, per se, drive the development of these diseases. Clinical studies comparing the ?metabolically healthy obese? to obese individuals with metabolic syndrome have revealed that the manner by which energy-storing white adipose tissue (WAT) remodels in obesity is a critical determinant of metabolic health. WAT ?remodeling? associated with obesity can be described as both quantitative and qualitative changes in adipocyte numbers and stromal/vascular cell composition. Pathologic WAT remodeling, tightly linked to insulin resistance, is characterized by inadequate expansion of adipocyte number (i.e. lack of adipogenesis), the presence of enlarged adipocytes, excessive macrophage accumulation, and fibrosis. The ensuing fat tissue dysfunction leads to the deleterious accumulation of lipids in non-adipose peripheral tissues. Healthy WAT remodeling involves hyperplastic adipose tissue expansion (increase in adipocyte number) and a lower degree of chronic tissue inflammation and fibrosis. These adipose phenotypes of the metabolically healthy obese tightly correlate with sustained insulin sensitivity. WAT remodeling is controlled by coordinated interactions between adipocytes, immune cells, and various types of poorly defined stromal/vascular cells. To date, the factors dictating a healthy vs. unhealthy WAT expansion in obesity remain unclear. We have identified a novel and distinct subpopulation of PDGFR?+ perivascular (mural) cells that exert a pro-inflammatory phenotype. We hypothesize that these cells, referred to as fibro-inflammatory progenitors (FIPs), serve as gatekeepers of adipose tissue inflammation and influence WAT remodeling. We propose to (1) characterize the frequency, function, and lineage plasticity of these cells across different adipose depots and physiological conditions influencing WAT remodeling (Aim 1), (2) define the importance of these cells: if and how mural cell inflammatory signaling influences adipose tissue remodeling and inflammation (Aim 2), and (3) evaluate the importance of the C2H2 zinc-finger transcription factor, ZFP423, in the control of mural cell inflammatory signaling (Aim 3). Successful completion of these aims will reveal a novel, physiologically regulated, population of perivascular cells in adult WAT that serve as gatekeepers of WAT inflammation. Further insight into the molecular determinants of healthy WAT expansion will lead to strategies to uncouple metabolic dysfunction from obesity.